Introduction to Toxicology

Richard R. Rediske, Ph.D.

Annis Water Resources Institute
Grand Valley State
University
 Toxicology
Formerly
The Science of Poisons

Now
The science that deals with the
adverse effects of chemicals on
living organisms and assesses
the probability of their
occurrence
 Outline
• History of Toxicology
• Dose Response
• Types of Toxicants
• Case Studies of alcohol and lead
• The Future
 Historical Perspective
“...the appearance of disease in human populations is influenced
by the quality of air, water, and food; the topography of the land;
and general living habits.”

The ancient-Greek physician Hippocrates

in his treatise Air, Water and Places
400 BC
http://classics.mit.edu/Hippocrates/airwatpl.m
b.txt
 All substances are poisons;
there is none that is not a poison.
The right dose
differentiates a poison and a remedy.

Paracelsus (1493-1541)
The Father of Modern
Toxicology
 History

Spanish physician Orfila (1815) established

toxicology as
a distinct scientific discipline.
 Toxicology Today
Mechanistic toxicology: The study of how a
chemical causes toxic effects by investigating its
absorption, distribution, and excretion.

Descriptive toxicology: The toxic properties of

chemical agents are systematically studied for
various endpoints using a variety of different
organisms.

Clinical toxicology: They study of toxic effects of

various drugs in the body, and are also concerned
with the treatment and prevention of drug toxicity in
the population.
 Toxicology Today
Forensic toxicology: A branch of
medicine that focuses on medical
evidence of poisoning, and tries to
establish the extent to which poisons

? were involved in human deaths.

Environmental toxicology: The study

of the effects of pollutants on organisms,
populations, ecosystems, and the
biosphere.

Regulatory toxicology: The use

scientific data to decide how to protect
humans and animals from excessive risk.
Public or Private Sector.
 Dose
The amount of chemical entering the body
This is usually given as
mg of chemical/kg of body weight = mg/kg
The dose is dependent upon
* The concentration
* The properties of the toxicant
* The timing and frequency of exposure
* The length of exposure
* The exposure pathway
 What is a Response?
The degree of responses depend upon the
dose and the organism
• Change from normal state
– could be on the molecular, cellular, organ, or
organism level--the symptoms
• Local vs. Systemic
• Reversible vs. Irreversible
• Immediate vs. Delayed
• Monotonic – response increases with dose (cyanide and
many traditional toxicants)
• Nonmonotic – response does not increase with dose
(hormones, endocrine disruptors, micronutrients and
vitamins)
 CHEMICALS: Major Types of Toxicity
• Toxins – biological compounds (Ricin, botulism)
• Carcinogens - may induce cancer or increase its
incidence and can affect any cells or tissues
(benzene, vinyl chloride, benzo(a)pyrene )
• Mutagen - may induce hereditary genetic defects or
increase their incidence and effect on the germ cells
(gonads). (radiation, nitrosoamines)
• Teratogens - may induce non-hereditary congenital
malformations or increase their incidence and
effect on the growing fetus (rubella, thalidomide,
PCBs, Dioxins)
• Endocrine disruptor – hormone mimic (PBDE, BPA)
 CHEMICALS: Major Types of Toxicity
• Chronic toxicity: It involves Sub-lethal
concentration and long-term exposure
• Chronic toxicity test is used to derive Effective
Dose (ED50): Is the dose by which half of the
population has been affected
• Effect could be anything but death
• ED50 is obtained by plotting, for a given dose
the proportion of the population that
responded to that dose and all lower doses
 CHEMICALS: Major Types of Toxicity

• Acute toxicity: It involves lethal concentrations and

short-term exposures
• The end point is usually death
• An LD50 is a dose of a toxic chemical that kills half of
the population.
• LD50 is obtained by plotting, for a given dose the
proportion of the population that responded to that
dose and all lower doses
Monotonic Dose Response
 CHEMICALS: Major Types of Toxicity
• No Observable Adverse Effect Level (NOAEL) –
the threshold where no effects are observed.
• Lowest Observable Adverse Effect Level
(LOAEL)
– the concentration level where effects are
observed.

ED50
Potency – concentration to produce an
effect.
 CHEMICALS: Major Types of Toxicity
Cancer causing chemicals are assessed by risk
• One mutation has an inherent risk so one molecule of a
toxicant may pose a theoretical risk.
• Organisms have repair functions for protection
• 1:1,000,000 risk is considered acceptable. (note: we
can only measure 1:100 in the laboratory and must
extrapolate the low risk level).
• Toxicity cannot be estimated by high dose experiments
Hormesis – U shaped dose response curve
(nonmonotonic)
• Characterized by a low dose stimulation or beneficial
effect and a high dose inhibitory or toxic effect.
• Essential nutrients, vitamins, ionizing radiation, aspirin,
alcohol
Dose Response Curves
 Endocrine disruptors:
• Synthetic or naturally occurring
chemicals that affect the Endocrine or
hormonal system of animals
• May either:
 Mimic hormones
 Block hormone activities
 Directly stimulate or inhibit the
endocrine system
 Hormones and Endocrine Disruptors
• Bind to receptor molecules
• Nonmonotonic dose response curves
• Stimulate at low doses
• No increasing effect at high doses due to receptor
saturation
• Very complex reactions and cross reactivity
• Very low doses are significant
• Effect cannot be estimated by high dose toxicity
testing
Endocrine Disruptors

Some chemicals, once inside

the bloodstream, can
“mimic” hormones.
If molecules of the chemical
bind to the sites intended
for hormone binding, they
cause an inappropriate
response.
Thus these chemicals disrupt
the endocrine (hormone)
system. Figure 10.5
Pearson Education Inc., 2005
http://maptest.rutgers.edu/drupal/?q=node/273
Vandenberg et al. 2012
http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors/AllPages
Populations
(Drugs of abuse)
 Ethanol

H H

H C C OH H

H
 Perceptions About Chemicals
• What drives our perceptions? Are
chemicals bad?

HUMAN RISK PERCEPTION... is affected by the degree of pleasure / displeasure

associated with the particular risk
 Agent LD-50 (mg/kg)
Ethyl alcohol 10,000
Salt (sodium chloride) 4,000
Iron (Ferrous sulfate) 1,500
Morphine 900
Mothballs 500
(paradichlorobenzene)
Aspirin 250
DDT 250
Cyanide 10
Nicotine 1
Tetrodotoxin (from fish) 0.01
Botulinum Toxin 0.00001
What type of toxic chemical is alcohol ?
• Group 1 known Human Carcinogen
• Exhibits hormesis – small amounts are
beneficial (cardiovascular system)
• Teratogen - fetal alcohol syndrome
“Of all the substances of abuse (including
cocaine, heroin, and marijuana), alcohol
produces by far the most serious
neurobehavioral effects in the fetus.”
—Institute of Medicine Report to Congress,
1996.
Fetal Alcohol Syndrome Facts
• Alcohol diffuses through placenta
• Concentration in fetal blood is the
same as in the mother’s blood
within a few minutes
• The fetus is able to metabolize
alcohol 10% as fast as the mother
• 1 in 200 individuals are affected by
prenatal alcohol exposure.
Sequence of Human Development

Black- most sensitive

 What is lead
• Lead is a soft gray metal element
that occurs naturally in the earth.

• For many years, lead was added

to
- paint,
- gasoline,
- Pipes and solder
- batteries

• Banned in 1973 in paint

• Banned in 1976 in gasoline
• Banned in solder in 1993
 What are the Sources of Lead
• Homes that have cracked and
peeling old lead paint on their
walls.

• Home renovations that disturb

old lead paint can spread invisible
lead dust.

• Lead from old lead paint may

contaminate household dust and
nearby soil.
 How are people exposed to lead?
• Ingestion of foods, water, alcohol
may be significant for certain
populations.
• Ingestion of dusts is primary way
general population, especially
children, are exposed to lead.

• Inhalation of lead dust

contributes to a build up in
the body.
 Childhood Risk Factors for
Elevated BLLs (>10μg/dl)
Pre-1946 Housing
Non-Hispanic Black 21.9%
Mexican American 13.0%
White 5.6%

Low Income 16.4%

High Income 0.9%

NHANES III, and CDC Recommendations for BL Screening of Young

Children (Dec. 2000)
 SOURCES OF LEAD-
House Dust

Uncontaminated- New inner-city home

Floor Surface-

2-24 µg/sq ft

Contaminated- Old inner-city home

Floor Surface-
33-486 µg/sq ft
How Does Lead Enter the Body?

Ingestion
Adults absorb about 6% of ingested lead.
Fasting adults absorb more.
Children absorb much more lead
(30-50% if well fed, and more, if fasting or
malnourished).
It takes >10 years to turn over one half the
body’s stored lead. Bone source slowly
leaches into the blood.
 Lead Exposure in utero

• Lead crosses the placenta in plasma.

• Pregnancy (and lactation) causes lead release
from bone stores into plasma
• Plasma lead is about 10% of circulating blood
lead.
• Epidemiologic effects on CNS have been
documented.
• Peak transfer is at 12-14 weeks
gestation
 Cognitive Performance Deficits
in Lead- Exposed Children
Deficits:
Psychomotor performance
Auditory and language processing
Sustained attention &
concentration
Measured outcomes:
Less likely to graduate High School
More likely to be convicted of felonies
What happens when lead enters the body
• Lead is stored for long periods in mineralizing tissue
such as teeth and bones.

• Lead is can be released again into the bloodstream

from these sources during times of bodily stress,
such as
~ pregnancy
~ breastfeeding
~ calcium deficiency
~ osteoporosis (thinning of the bones)
 Lead Exposure
• Most lead exposure in the
U.S. today occurs in older
homes with deteriorated
leaded paint.
• Children are at greatest risk
of lead poisoning from their
homes.
• Most children are exposed to
lead in dust
(not by eating paint chips).
Lead in home environments (continued)
 Lead in home dust
• The more lead in the dust in a home, the
higher the levels of lead in children.
• There is no safe threshold for lead.

walls
windows
doors
bare soil
Lead in dust

porch tracked in
 What parts of the body does lead affect?

• The brain is very sensitive to lead.

• Exposure to high levels of lead can permanently
affect the brain, bones, kidneys, and the heart.
 What levels cause health effects
• Lead can cause harm even at very low levels,
especially in young children.
• There is no safe threshold
for lead.
• At very high levels, lead can cause
brain damage, coma or
even
• Adults experience similar death.
effects, but generally at
higher levels of exposure.
 What are the effects of lead exposure on
young children?

• Lowered IQ
• Learning disabilities
• Attention deficit and hyperactivity
• Other behavioral issues
• Impaired hearing
• Anemia
• Decreased growth
 How to test for lead exposure
• Children should have their
blood tested at ages one and
two.

• Older children at risk of lead

poisoning should also be
tested.

• Adults who may be exposed

to lead at work should also
be tested.
 How to prevent lead exposure
• If your home was built before 1978, you
should have it tested for lead.

• Make sure all paint is in good condition.

• Wet-clean all surfaces, especially window

sills, at least every week.

• Wash children’s hands frequently.

• Cover bare soil in the yard.

• Learn about lead-safe work practices when

doing work on your home that disturbs
paint.
Toxicants take many routes through the
environment often as mixtures.
 What is the role of Toxicology in
Green Chemistry
• Linking molecular structure to hazard
• Focus less on minimizing risk through reducing
exposure
• Focus more on minimizing hazard by designing safer
chemicals
• Risk = Hazard x Dose (Exposure)
• The hazardous nature of a substance can be controlled
through structure manipulation
Approaches

Voutchkova et al 2009

Schug et al 2012
Estrogen vs Hormonally Active Agents

mindfully.org
 Summary
• Toxicology is a complex science based on the
principle of dose and response.
• Environmental exposures further adds to this
complexity.
• Focus more on minimizing hazard by designing
safer chemicals
• Green chemistry can provide solutions!
 Summary
Toxicology is a fascinating science that makes biology and
chemistry interesting and relevant.

Understanding HOW (i.e. mechanism)

something produces a toxic effect can lead to new ways of
preventing or treating chemically-related diseases. Animal
use in research is essential for medical progress.

Many diseases are the result of an interaction between our

genetics (individual variability) and chemicals in our
environment.

Toxicology provides an interesting and exciting way to apply

science to important problems of social, environmental,
and public health significance.
 Your Role
Risk is a part of everyday life, and
one’s decisions as to the
‘acceptability’ of a particular risk
is influenced by knowledge.

We can try to increase the public’s

knowledge about the risks and
benefits of all things chemical.

You play a critical role in this effort, and

we can’t do it without YOU.